Mechanisms of Axonal Degeneration in Traumatic Injury and Neurological Disease

创伤性损伤和神经系统疾病中轴突变性的机制

• 批准号: 7674866
• 负责人: Martha Ruth Chase Bhattacharya
• 金额: $ 4.72万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2011-09-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674866
• 关键词: Adverse effects; Affect; Animal Disease Models; Animal Model; Apoptosis; Axon; Axonal Transport; Biochemistry; Biological Preservation; Carrier Proteins; Cellular Assay; Chimeric Proteins; Clinical; Code; Confocal Microscopy; Diabetes Mellitus; Disease; Dissociation; Dose-Limiting; Enzymes; Excision; Genes; Glaucoma; Health Benefit; Healthcare Systems; In Vitro; Infection; Injury; JNK-activating protein kinase; Kinesin; MAP Kinase Kinase Kinase; MAPK8 gene; Microtubules; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Motors; Multiple Sclerosis; Mus; Mutation; Nerve; Nerve Degeneration; Neurons; Optic Nerve; Parkinson Disease; Pathology; Pathway interactions; Patients; Phosphotransferases; Prevention; Process; Proteins; Public Health; Quality of life; Regulation; Research; Retinal Ganglion Cells; Role; Signal Transduction; Symptoms; Synapses; System; Testing; Therapeutic; Transgenic Mice; anterograde transport; axonal degeneration; design; fly; improved; in vivo; inhibitor/antagonist; injured; insight; knockout animal; mouse model; nervous system disorder; prevent; programs; protective effect; somatosensory; therapy development

DESCRIPTION (provided by applicant): Axon degeneration contributes to the pathologies of diabetes, glaucoma, and Parkinson's Disease, and is the dose-limiting side effect of chemotherapeutic treatments. It is an actively regulated program similar to apoptosis but distinct in its execution mechanisms. Cellular programs controlling the preservation and destruction of axons are not well understood, and we do not currently have therapies to prevent such degeneration. Development of therapies to treat or prevent axon degeneration could significantly improve the quality of life for patients with the above disorders while also reducing the burden they place on our health care system. Two genes are currently known to influence axon degeneration in neurons: Wlds, and the MAP kinase DLK. Inhibition of DLK or its downstream kinase JNK significantly delay axon degeneration in injury models. I propose to investigate the cellular mechanisms controlled by DLK that allow this delay. I will culture primary somatosensory neurons in vitro, injure axons in culture, and use cellular assays, confocal microscopy, and biochemistry to ask how DLK regulates microtubules, axon transport, and other pathways affected by axon degeneration. The intersection of the DLK and Wlds pathways will also be examined, as these two control mechanisms may act in an additive manner and could provide additional insight into designing molecular therapies for axon degeneration. For this aim we will use already established transgenic mice and lentiviral infection of neurons in vitro and in vivo. Finally, I will test whether DLK or JNK inhibition control degeneration in axons of retinal ganglion cells (RGCs) comprising the optic nerve, as these axons undergo degeneration during glaucoma. Both in vitro studies of RGCs and in vivo injury models, as well as established mouse models of glaucoma, will be used to ask whether DLK and/or Wlds exert protective effects in this system and whether DLK pathway inhibition may be an appropriate therapeutic strategy for glaucoma. Understanding axon degeneration will have significant public health benefits due to the broad spectrum of diseases where axon degeneration causes symptoms. Our research seeks to determine effective avenues for delay or prevention of axon degeneration that could be used in clinical settings

描述（由申请人提供）：轴突变性导致糖尿病、青光眼和帕金森病的病理学，并且是化疗治疗的剂量限制性副作用。它是一种类似于细胞凋亡的主动调控程序，但其执行机制不同。控制轴突保存和破坏的细胞程序尚不清楚，而且我们目前没有预防这种退化的疗法。开发治疗或预防轴突变性的疗法可以显着改善患有上述疾病的患者的生活质量，同时也减轻他们给我们的医疗保健系统带来的负担。目前已知有两个基因会影响神经元的轴突变性：Wlds 和 MAP 激酶 DLK。抑制 DLK 或其下游激酶 JNK 可显着延缓损伤模型中的轴突变性。我建议研究 DLK 控制的允许这种延迟的细胞机制。我将在体外培养原代体感神经元，在培养物中损伤轴突，并使用细胞测定、共聚焦显微镜和生物化学来探究 DLK 如何调节微管、轴突运输和其他受轴突变性影响的途径。 DLK 和 Wlds 途径的交叉点也将被检查，因为这两种控制机制可能以相加的方式起作用，并且可以为设计轴突变性的分子疗法提供额外的见解。为此，我们将使用已经建立的转基因小鼠和体外和体内神经元的慢病毒感染。最后，我将测试 DLK 或 JNK 抑制是否控制构成视神经的视网膜神经节细胞 (RGC) 轴突的退化，因为这些轴突在青光眼期间会发生退化。 RGC 和体内损伤模型的体外研究，以及已建立的青光眼小鼠模型，都将用于询问 DLK 和/或 Wlds 是否在该系统中发挥保护作用，以及 DLK 通路抑制是否可能是青光眼的适当治疗策略。青光眼。由于轴突变性引起症状的疾病范围广泛，了解轴突变性将对公共健康产生重大益处。我们的研究旨在确定可用于临床环境的延迟或预防轴突变性的有效途径